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Combination protocols of cytokine therapy with interleukin-3 and
granulocyte-macrophage colony-stimulating factor in a primate model of
radiation-induced marrow aplasia
AM Farese, DE Williams, FR Seiler and TJ MacVittie
Experimental Hematology Department, Armed Forces Radiobiology Research
Institute, Bethesda, MD 20889-5603.
Single cytokine therapy with granulocyte-macrophage colony-stimulating
factor (GM-CSF) or interleukin-3 (IL-3) has been shown to be effective in
decreasing the respective periods of neutropenia and thrombocytopenia
following radiation- or drug-induced marrow aplasia. The combined
administration of IL-3 and GM-CSF in normal primates suggested that a
sequential protocol of IL-3 followed by GM-CSF would be more effective than
that of GM-CSF alone in producing neutrophils (PMN). We investigated the
therapeutic efficacy of two combination protocols, the sequential and
coadministration of recombinant human IL- 3 and GM-CSF relative to
respective single cytokine therapy, and delayed GM-CSF administration in
sublethally irradiated rhesus monkeys. Monkeys irradiated with 450 cGy
(mixed fission neutron:gamma radiation) received either IL-3, GM-CSF, human
serum albumin (HSA), or IL-3 coadministered with GM-CSF for days 1 through
21 consecutively postexposure, or IL-3 or HSA for days 1 through 7 followed
by GM-CSF for days 7 through 21. All cytokines and HSA were injected
subcutaneously at a total dose of 25 micrograms/kg/d, divided twice daily.
Complete blood counts (CBC) and platelet (PLT) counts were monitored over
60 days postirradiation. The respiratory burst activity of the PMN was
assessed flow cytometrically, by measuring hydrogen peroxide (H2O2)
production. Coadministration of IL-3 and GM-CSF reduced the average 16-day
period of neutropenia and antibiotic support in the control animals to 6
days (P = .006). Similarly, the average 10-day period of severe
thrombocytopenia, which necessitated PLT transfusion in the control
animals, was reduced to 3 days when IL-3 and GM-CSF were coadministered (P
= .004). The sequential administration of IL-3 followed by GM-CSF had no
greater effect on PMN production than GM-CSF alone and was less effective
than IL-3 alone in reducing thrombocytopenia. PMN function was enhanced in
all cytokine-treated animals.
Volume 82,
Issue 10,
pp. 3012-3018,
11/15/1993
Copyright © 1993 by The American Society of Hematology
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